Application of targeted next generation sequencing for the mutational profiling of patients with acute lymphoblastic leukemia.

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children, whereas it is less common in adults. Identification of cytogenetic aberrations and a small number of molecular abnormalities are still the most important risk and therapy stratification methods in clinical practice today. Next generation sequencing (NGS) technology provides a large amount of data contributing to elucidation of mutational landscape of childhood (cALL) and adult ALL (aALL).

Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment.

Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions.

Influence of variants in folate metabolism genes on 6-mercaptopurine induced toxicity during treatment for childhood acute lymphocytic leukemia.

Purpose: To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL).

Methods: One-hundred twenty-seven children with ALL that received maintenance therapy were involved in this study. All patients were treated according to Berlin-Frankfurt-Muenster (BFM) based protocols.

Expression Pattern of Long Non-coding RNA Growth Arrest-specific 5 in the Remission Induction Therapy in Childhood Acute Lymphoblastic Leukemia.

Background: Long non-coding RNA growth arrest-specific 5 () is deregulated in many cancers because of its role in cell growth arrest and apoptosis. Additionally, interacts with glucocorticoid receptor, making it a potential pharmacotranscription marker of glucocorticoid (GC) therapy. In this study, we aimed at analysing expression in the remission induction therapy phase of childhood acute lymphoblastic leukemia (ALL), in which GCs are mandatorily used, and to correlate it with therapy response.

Variants in TPMT, ITPA, ABCC4 and ABCB1 Genes As Predictors of 6-mercaptopurine Induced Toxicity in Children with Acute Lymphoblastic Leukemia.

Background: Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia.

Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia.

Background Response to glucocorticoid (GC) monotherapy in the initial phase of remission induction treatment in childhood acute lymphoblastic leukemia (ALL) represents important biomarker of prognosis and outcome. We aimed to study variants in several pharmacogenes (NR3C1, GSTs and ABCB1) that could contribute to improvement of GC response through personalization of GC therapy. Methods Retrospective study enrolling 122 ALL patients was carried out to analyze variants of NR3C1 (rs33389, rs33388 and rs6198), GSTT1 (null genotype), GSTM1 (null genotype), GSTP1 (rs1695 and rs1138272) and ABCB1 (rs1128503, rs2032582 and rs1045642) genes using PCR-based methodology.

Lymphoblastic lymphomas in children – A single-center experience from Serbia.

Introduction: Intensive treatment protocols used for non-Hodgkin lymphoma in children lead to eventfree survival rates ranging from 80% to 90%. However, the results are less successful in developing countries. Lymphoblastic lymphoma (LBL) is the second most frequent type of lymphoma in children, contributing with about one third to all non-Hodgkin lymphoma in childhood.

Extreme Hypertriglyceridemia in an Infant with Hemophagocytic Lymphohistiocytosis and Hydroxycobalamin Deficiency.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory condition characterized by fever, cytopenias, hepatosplenomegaly and hemophagocytosis. HLH may be primary or secondary to infection, autoimmune disease or malignancy. Hypertriglyceridemia is a common abnormality in HLH and one of the HLH-2004 diagnostic criteria.

TPMT gene expression is increased during maintenance therapy in childhood acute lymphoblastic leukemia patients in a TPMT gene promoter variable number of tandem repeat-dependent manner.

Aims: 6-mercaptopurine influences in vitro TPMT gene expression in a TPMT promoter variable number of tandem repeats (VNTR)-dependent manner. We studied TPMT expression following 6-mercaptopurine and methotrexate administration in childhood acute lymphoblastic leukemia (ALL) patients and the pharmacogenomic potential of the VNTR architecture.

Materials & Methods: TPMT gene expression was determined in childhood ALL patients at diagnosis (n = 57) and during the maintenance therapy (n = 27).

Hemophagocytic lymphohistiocytosis arising in a child with Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is characterized by the proliferation of clonal dendritic cells, while hemophagocytic lymphohistiocytosis (HLH) is an extreme inflammatory process sustained by the uncontrolled activation of macrophages. HLH can be primary or secondary, the latter arising in infectious, autoimmune or neoplastic disorders. We hereby present a young girl who developed secondary HLH while being treated for relapsed multisystem LCH under the LCH III Protocol.

Non-Hodgkin lymphomas in childhood: how to move on?

Non-Hodgkin lymphomas of childhood represent a diverse group of neoplasms with different clinical, pathological, immunophenotypical and genetic features. A vast majority of childhood non-Hodgkin lymphomas could be classified into one of the three major histological subgroups: mature B-cell neoplasms, lymphoblastic lymphomas or anaplastic large cell lymphomas. Modern therapeutic strategies lead to cure in more than 80% of patients.

Colon carcinoma in a child treated with oxaliplatin and antiangiogenic treatment regimens.

Colorectal carcinoma is an extremely rare tumor in childhood. Therefore, the role of adjuvant chemotherapy has not been adequately evaluated in children leading to limited data on safety profile and treatment response after application of novel drugs and novel targeted agents. In this report, we describe a case of colon adenocarcinoma in a 13-year-old girl treated with standard adult treatment as well as novel targeted therapy.

[Clinical characteristics and disease course in children with haemophagocytic lymphohistiocytosis treated at the University Children's Hospital in Belgrade].

Introduction: Haemophagocytic lymphohistiocytosis (HLH) is a disorder characterised by long-standing fever, splenomegaly and bicytopoenia or pancytopoenia. Lymphadenopathy, jaundice and neurological symptoms mayalsooccur. HLH may ensue in various forms of innate or acquired immunodeficiency with impaired cytotoxic lymphocyte function resulting in excessive macrophage activation.

Pediatric non-Hodgkin lymphoma: a retrospective 14-year experience with Berlin-Frankfurt-Münster (BFM) protocols from a tertiary care hospital in Serbia.

Use of current intensive chemotherapy protocols in pediatric non-Hodgkin lymphoma (NHL) in high-income countries resulted in event-free survival (EFS) rates ranging from 80 to 90%. The results are inferior in less privileged countries with limited resources for medical care. There are no reports about comprehensive data analysis in pediatric NHL in Serbia.

6-mercaptopurine influences TPMT gene transcription in a TPMT gene promoter variable number of tandem repeats-dependent manner.

Aim: TPMT activity is characterized by a trimodal distribution, namely low, intermediate and high methylator. TPMT gene promoter contains a variable number of GC-rich tandem repeats (VNTRs), namely A, B and C, ranging from three to nine repeats in length in an A(n)B(m)C architecture. We have previously shown that the VNTR architecture in the TPMT gene promoter affects TPMT gene transcription.

Late vitamin K deficiency bleeding in an infant with choledochal cyst.

Infantile choledochal cyst (CC) usually presents as jaundice, vomiting, acholic stools, and hepatomegaly, and it can resemble biliary atresia. Although bleeding tendency is a rare clinical presentation of CC, it can be the first symptom, especially in infants less than 12 months of age. We report a case of a two-month-old infant with choledochal cyst presenting as late vitamin K deficiency bleeding (VKDB).

[Immunoglobulin genes and T-cell receptors as molecular markers in children with acute lymphoblastic leukaemia].

Introduction: Acute lymphoblastic leukaemia (ALL) is a malignant clonal disease, one of the most common malignancies in childhood. Contemporary protocols ensure high remission rate and long term free survival. The ability of molecular genetic methods help to establish submicroscopic classification and minimal residual disease (MRD) follow up, in major percent responsible for relapse.

[Rehabilitation in haemophilic children with inhibitors using recombinant activated factor VII].

Introduction: During invasive and orthopaedic procedure of the joints, physical therapy is a necessary modality for successful recovery, especially in patients with haemophilia. These patients require concurrent substitution therapy. Recombinant activated factor VII (rFVIIa) has been successfully used in treating haemophilia with inhibitor, especially during preoperative preparation.

[Treatment of psoas haematoma in a patient with haemophilia and inhibitors].

Introduction: Particular problem in treating haemophiliacs with serious muscle bleeding such as iliopsoas haematoma, are patients with inhibitor.

Case Outline: Our study describes three episodes of psoas haematoma in a patient with haemophilia and inhibitor successfully treated with recombinant activated factor VII (rFVIIa).

Conclusion: Based on our experience, initiating therapy within two hours in our patient, contributed to successful treatment, although small cumulative doses of rFVIIa were used.

Incidence of FLT3 and nucleophosmin gene mutations in childhood acute myeloid leukemia: Serbian experience and the review of the literature.

Mutations in the fms-like tyrosine kinase 3 (FLT3) gene (internal tandem duplication (ITD) and point mutation in the tyrosine kinase domain, FLT3/D835) as well as the nucleophosmin (NPM1) gene are the most common abnormalities in adult acute myeloid leukemia (AML). Their significance in pediatric AML is still unclear. In this study we evaluated the frequency of FLT3 and NPM1 mutations in childhood AML.

[Hyper-IgM syndrome in a boy with recurrent pneumonia and hepatosplenomegaly].

Introduction: We present a boy diagnosed at age 14 years with hyper-immunoglobulin (Ig) M syndrome, a congenital immunodeficiency characterized by reduced plasma concentrations of IgA, IgE and IgG, with normal or elevated concentrations of IgM. This syndrome is caused by a defect of CD40 ligand (CD40L) on T-helper lymphocytes, impeding the "second signal" during activation of B lymphocytes and interactions of T cells with dendritic cells and macrophages, resulting in the absence of secondary immune response (class switching, affinity maturation, immune memory), as well as responses to T-dependent antigens, with an impairment of cellular immunity.

Case Outline: The history of the presented patient was dominated by frequent lower respiratory infections and failure to thrive.

[Importance of genotyping of thiopurine S-methyltransferase in children with acute lymphoblastic leukaemia during maintenance therapy].

Introduction: Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyses the inactivation of mercaptopurine (MP) which is widely used in the treatment of acute lymphoblastic leukaemia (ALL) of childhood. Potentially fatal myelotoxicity may develop after standard doses of MP in TPMT deficient patients.

Objectives: To establish if individually tailored doses of MP can reduce myelotoxicity in ALL patients carrying mutations in the TPMT gene.

[Clinical characteristics and survival of children with hepatoblastoma--single centre experience].

Introduction: Hepatoblastoma is the most frequent malignant liver tumour of childhood and it accounts for 1% of all paediatric cancers. The outcome is significantly improved by introducing intensive chemotherapy regimens followed by complete surgical tumour resection. The long-term survival is 75-95% at present.

Ruptured intramural intestinal hematoma in an adolescent patient with severe hemophilia A.

We report on a 17-year-old patient with severe hemophilia A without inhibitors who developed abdominal bleeding after an episode of severe cough. Abdominal ultrasound showed intramural intestinal hematoma as well as large amount of peritoneal fluid appearing as blood and right hematocele. Abdominal CT revealed markedly thickened intestinal wall in sigmoidal region.